Parkinsonism is a common clinical problem affecting the daily activities of hundreds of thousands of patients. This proposal will idnetify genes and their protein products that contribute to the etiology of this important entity. Parkinson's Disease (PD) is characterized by the specific loss of neurons in the substantia nigra. Therefore, the hypothesis of Project II: Generation and Analysis of Candidate Genes from the Substantia Nigra, is that a problem in the expression of a gene or genes in this tissue contributes to the etiology of these disorders. This will be investigated using the recently described Serial Analysis of Gene Expression (SAGE) methodology utilizing tissue from normals, PD with Lewy bodies and Frontotemporal Dementia with Parkinson's (FTDP). A unique aspect of this program project is the ability to test the specificity of the subsequently identified gene products using a genetic framework. Identified genes from this project will be used as candidate genes for Project I: The Genetics of Parkinson's Disease. The purpose of this project is to identify the gene or genes contributing to the etiology of sporadic PD. Sporadic PD patients will be investigated using new and exciting methodologies, S-TDT/SDT, looking for genetic associations in the PD patients using the SAGE and other candidate genes. It will also incorporate data from an ongoing linkage analysis of multiplex PD families. Project III: Genetic and Environmental Factors in Parkinson's Disease, continues to concentrate on dissecting the complex etiology of PD, collecting environmental data and seeking gene-environmental interaction. Three Cores will support this work: Family Ascertainment and Clinical, Neuropathological, and Statistical analysis and Informatics.